β-Arrestin-1 Competitively Inhibits Insulin-Induced Ubiquitination and Degradation of Insulin Receptor Substrate 1

Abstract

␤-Arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous desensitization between receptor tyrosine kinases and GPCR signaling. In the present study, we determined whether ␤-arrestin-1 is involved in insulin-induced insulin receptor substrate 1 (IRS-1) degradation. Overexpression of wild-type (WT) ␤-arrestin-1 attenuated insulin-induced degradation of IRS-1, leading to increased insulin signaling downstream of IRS-1. When endogenous ␤-arrestin-1 was knocked down by transfection of ␤-arrestin-1 small interfering RNA, insulin-induced IRS-1 degradation was enhanced. Insulin stimulated the association of IRS-1 and Mdm2, an E3 ubiquitin ligase, and this association was inhibited to overexpression of WT ␤-arrestin-1, which led by decreased ubiquitin content of IRS-1, suggesting that both ␤-arrestin-1 and IRS-1 competitively bind to Mdm2. In summary, we have found the following: (i) ␤-arrestin-1 can alter insulin signaling by inhibiting insulin-induced proteasomal degradation of IRS-1; (ii) ␤-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2, an E3 ligase that can ubiquitinate IRS-1; (iii) dephosphorylation of S412 on ␤-arrestin and the amino terminus of ␤-arrestin-1 are required for this effect of ␤-arrestin on IRS-1 degradation; and (iv) inhibition of ␤-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance.␤-Arrestins are versatile adaptor proteins that form complexes with most seven-transmembrane receptors (7TMR) following agonist binding and receptor phosphorylation by Gprotein-coupled receptor kinases. Binding of ␤-arrestin to the 7TMR cytoplasmic domain interrupts further heterotrimeric G-protein interaction with the receptor, causing signal termination. ␤-arrestin also mediates endocytosis and receptor sequestration, further enhancing desensitization of receptor signaling (1,17,(19)(20)(21)27). ␤-Arrestin can also play a role as a 7TMR signal transducer by recruiting activated Src to the receptor complex, leading to mitogen-activated protein kinase activation (6,7,18,19). We have also reported that ␤-arrestin can play an important role in the process of heterologous desensitization of receptor tyrosine kinases (RTKs), as well as 7TMRs. Thus, insulin treatment leads to ␤-arrestin-1 Ser412 phosphorylation, ubiquitination, and degradation, all of which impair mitogen-activated protein kinase phosphorylation mediated by G␣ i-coupled receptors, such as the lysophosphatidic acid (LPA) receptor, ␤ 2 -adrenergic receptor (␤ 2 -AR), and the insulin-like growth factor I (IGF-I) receptor (4).Since ␤-arrestin is involved in homologous G-protein-coupled receptor (GPCR) desensitization, as well as insulin-induced heterologous desensitization of G␣ i-coupled receptor signaling, we wondered whether ␤-arrestin could also function in the process of insulin-induced homologous desensitization.It is well known t...

β-Arrestin-1 Protein Represses Diet-induced Obesity

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Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21

“…Although these siRNA's have been used to specifically knockdown arrestin 2 or arrestin 3 in human cells (41,52,53), in the HuT 78 cells used in this study, both arrestin 2 and arrestin 3 levels were reduced by the siRNA for arrestin 3. Therefore, it was unclear whether loss of internalization of CCR7/CCL19 in the arrestin 3 siRNA-treated cells was due to a reduction in the levels of arrestin 3 alone, or due to the loss of both arrestin 2 and arrestin 3 combined.…”

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